Advertisement

Serum levels of insulin-like growth factor-I,-II and insulin-like growth factor binding proteins-2 and-3 in children with acute lymphoblastic leukaemia

  • Klaus L. Mohnike
  • Ute Kluba
  • Uwe Mittler
  • Volker Aumann
  • Peter Vorwerk
  • Werner F. Blum
Endocrinology

Abstract

Abstract

The insulin-like growth factor (IGF) signaling pathway may be of importance for the proliferation of different tumours (e.g. breast cancer and Wilms tumour). The bioavailability of both IGF-I and IGF-II is regulated by specific IGF-binding proteins (IGFBPs). IGFBP-2 is the predominant binding protein during fetal life, where it is expressed in most tissues. In contrast, postnatally it is mainly released by specific cell types (hepatocytes, astroglia, kidney cells, prostate cells) and a range of tumour cell lines. Furthermore, phytohaemagglutinin stimulated normal lymphoblasts and malignant lymphoblasts express IGFBP-2. In order to investigate the IGF regulatory pathway in leukaemia serum levels of IGF-I, IGF-II, IGFBP-2 and IGFBP-3 were determined in 28 leukaemic children. Whereas serum levels of IGF-I (mean/range: −2.7/−0.1 to −6.7 SDS), IGF-II (−3.6 SDS/−1.3 to −8.7) and IGFBP-3 (−2.0/+2.2 to −7.1 SDS) were significantly decreased comparable to levels in growth hormone deficiency, IGFBP-2 levels (+4.0/−0.45 to +7.4 SDS) were found to be markedly elevated and inversely correlated to IGF-I (r=−0.51,P=0.013). After haematological remission upon chemotherapy all four parameters had normalized in the 16 re-investigated children. Similar findings have been observed in one boy with a relapse including CNS leukaemia.

Conclusion

This study demonstrates that the proliferation of malignant lymphoblasts (at diagnosis vs treatment) occurs in the presence of decreased serum levels of IGF-I, IGF-II and IGFBP-3 and that diminished production of these peptides may contribute to impaired growth. It further indicates that serum levels of IGFBP-2 may be directly related to the proliferation of lymphoblasts.

Key words

Growth regulation Leukaemia Radioimmunoassay Insulin-like growth factors Insulin-like growth factor-binding proteins 

Abbreviations

ALL

acute lymphoblastic leukaemia

BFM

Berlin Frankfurt Münster, protocol for the treatment of childhood ALL

GH

growth hormone

IGF

insulin-like growth factor

IGFBP

insulin-like growth factor binding protein

References

  1. 1.
    Adamo ML, Shao ZM, Lanau F, Chen JC, Clemmons DR, Roberts CTI, LeRoith D, Fontana JA (1992) Insulin-like growth factor-I (IGF-I) and retinoic acid modulation of IGF-binding proteins (IGFBPs): IGFBP-2,-3, and-4 gene expression and protein secretion in a breast cancer cell line. Endocrinology 131: 1858–1866PubMedCrossRefGoogle Scholar
  2. 2.
    Babajko S, Hardouin S, Segovia B, Groyer A, Binoux M (1993) Expression of insulin-like growth factor binding protein-1 and-2 genes through the perinatal period in the rat Endocrinology 132:2586–2592PubMedCrossRefGoogle Scholar
  3. 3.
    Baker J, Liu JP, Robertson EJ, Efstratiadis A (1993) Role of insulin-like growth factors in embryonic and postnatal growth. Cell 75:73–82PubMedGoogle Scholar
  4. 4.
    Ballard J, Baxter R, Binoux M, M, Clemmons D, Drop S, Hall K, Hintz R, Rechler M, Rutanen E, Schwander J (1989) On the nomenclature of the IGF binding proteins [letter]. Acta Endocrinol Copenh 121:751–752PubMedGoogle Scholar
  5. 5.
    Bar RS, Boes M, Clemmons DR, Busby WH, Sandra A, Dake BL, Booth BA (1990) Insulin differentially alters transcapillary movement of intravascular IGFBP-1, IGFBP-2 and endothelial cell IGF-binding proteins in the rat heart. Endocrinology 127:497–499PubMedCrossRefGoogle Scholar
  6. 6.
    Baserga R, Porcu P, Sell C, (1993) Oncogenes, growth factors and control of the cell cycle. Cancer Surv 16:201–213PubMedGoogle Scholar
  7. 7.
    Binoux M, Roghani M, Hossenlopp P, Hardoain S, Gourmelen M (1991) Molecular forms of human IGF binding proteins: physiological implications. Acta Endocrinol Copenh 124 [Suppl 2]:41–47PubMedGoogle Scholar
  8. 8.
    Blum WF, Ranke MB, Bierich JR (1988) A specific radioimmunoassay for insulin-like growth factor II: the interference of IGF binding proteins can be blocked by excess IGF-I. Acta Endocrinol Copenh 118: 374–380PubMedGoogle Scholar
  9. 9.
    Blum WF, Jenne EW, Reppin F, Kietzmann K, Ranke MB, Bierich JR (1989) Insulin-like growth factor I (IGF-I)-binding protein complex is a better mitogen than free IGF-I. Endocrinology 125:766–772PubMedGoogle Scholar
  10. 10.
    Blum WF, Ranke MB, Kietzmann K, Gauggel E, Zeisel HJ, Bierich JR (1990) A specific radioimmunoassay for the growth hormone (GH)-dependent somatomedin-binding protein: its use for diagnosis of GH deficiency. J Clin Endocrinol Metab 70: 1292–1298PubMedGoogle Scholar
  11. 11.
    Blum WF, Ranke MB (1992) Insulin-like growth factors and their binding proteins. In: Blum WF, Ranke MB (eds) Functional endocrinologic diagnostics in children and adolescents. J and J Verlag, Mannheim, pp 102–118Google Scholar
  12. 12.
    Blum WF, Horn N, Kratzsch J, Jorgensen JO, Juul A, Teale D, Mohnike K, Ranke MB (1993) Clinical studies of IGFBP-2 by radioimmunossay. Growth Regul 3: 100–104PubMedGoogle Scholar
  13. 13.
    Breier BH, Milsom SR, Blum WF, Schwander J, Gallaher BW, Gluckman PD (1993) Insulin-like growth factors and their binding proteins in plasma and milk after growth hormone-stimulated galactopoiesis in normally lactating women. Acta Endocrinol Copenh 129:427–435PubMedGoogle Scholar
  14. 14.
    Brunner N, Yee D, Kern FG, Spang-Thomsen M, Lippman ME, Cullen KJ (1993) Effect of endocrine therapy on growth of T61 human breast cancer xenografts is directly correlated to a specific down-regulation of insulin-like growth factor II (IGF-II). Eur J Cancer 29A: 562–569PubMedCrossRefGoogle Scholar
  15. 5.
    Chard T, Blum WF, Brunjes J, Campbell DJ, Wathen NC (1994) Levels of insulin-like growth factor-binding protein-2 and insulin-like growth factor-II in maternal serum, amniotic fluid and extraembryonic coelomic fluid at 9–20 weeks of pregnancy. J Endocrinol 142: 379–383PubMedCrossRefGoogle Scholar
  16. 16.
    Clemmons DR (1991) Insulin-like growth factor binding proteins: roles in regulating IGF physiology. J Dev Physiol 15: 105–110PubMedGoogle Scholar
  17. 17.
    Clemmons DR (1991) Insulin-like growth factor binding proteins. In: LeRoith D (ed) Insulin-like growth factors: molecular and cellular aspects. CRC Press Ann Arbor, Boston, pp 151–180Google Scholar
  18. 18.
    Clemmons DR, Cascieri MA, Camacho-Hubner C, McCusker RH, Bayne ML (1990) Discrete alterations of the insulin-like growth factor I molecule which alter its affinity for insulin-like growth factor-binding proteins result in changes in bioactivity. J Biol Chem 265: 12210–12216PubMedGoogle Scholar
  19. 19.
    Clemmons DR, Jones JI, Busby WH, Wright G (1993) Role of insulin-like growth factor binding proteins in modifying IGF actions. Ann N Y Acad Sci 692: 10–21PubMedCrossRefGoogle Scholar
  20. 20.
    Cohick WS, Clemmons DR (1993) The insulin-like growth factors. Annu Rev Physiol 55: 131–153PubMedCrossRefGoogle Scholar
  21. 21.
    Dahn MS, Lange MP, Jacobs LA (1988) Insulinlike growth factor 1 production is inhibited in human sepsis. Arch Surg 123: 1409–1414PubMedGoogle Scholar
  22. 22.
    Daughaday WH, Deuel TF (1991) Tumor secretion of growth factors. Endocrinol Metab Clin North Am 20: 539–563PubMedGoogle Scholar
  23. 23.
    Delhanty PJ, Han VK (1993) The expression of insulin-like growth factor (IGF)-binding protein-2 and IGF-II genes in the tissues of the developing ovine fetus. Endocrinology 132: 41–52PubMedCrossRefGoogle Scholar
  24. 24.
    Delhanty PJ, Hill DJ, Shimasaki S, Han VK (1993) Insulin-like growth factor binding protein-4,-5 and-6 mRNAs in the human fetus: localization to sites of growth and differentiation? Growth Regul 3: 8–11PubMedGoogle Scholar
  25. 25.
    Drop SL (1991) Report on the nomenclature of te IGF binding proteins. Acta Endocrinol Copenh 125: 707–708PubMedGoogle Scholar
  26. 26.
    Gansler T, Furlanetto R, Gramling TS, Robinson KA, Blocker N, Buse MG, Sens DA, Garvin AJ (1989) Antibody to type I insulinlike growth factor receptor inhibits growth of Wilms' tumor in culture and in athymic mice.Google Scholar
  27. 27.
    Gibson LF, Piktel D, Landreth KS (1993) Insulin-like growth factor-1 potentiates expansion of interleukin-7-dependent pro-B cells. Blood 82: 3005–3011PubMedGoogle Scholar
  28. 28.
    Han VK, D'Ercole AJ, Lund PK (1987) Cellular localization of somatomedin (insulin-like growth factor) messenger RNA in the human fetus. Science 236: 193–197PubMedCrossRefGoogle Scholar
  29. 29.
    Humbel RE (1990) Insulin-like growth factors I and II. Eur J Biochem 190: 445–462PubMedCrossRefGoogle Scholar
  30. 30.
    Kanety H, Madjar Y, Dagan Y, Levi J, Papa MZ, Pariente C, Goldwasser B, Karasik A (1993) Serum insulin-like growth factor-binding protein-2 (IGFBP-2) is increased and IGFBP-3 is decreased in patients with prostate cancer: correlation with serum prostate-specific antigen. J Clin Endocrinol Metab 77: 229–233PubMedCrossRefGoogle Scholar
  31. 31.
    Lee PD, Rosenfeld RG, Hintz RL, Smith SD (1986) Characterization of insulin, insulin-like growth factors I and II, and growth hormone receptors on human leukemic lymphoblasts. J Clin Endocrinol Metab 62: 28–35PubMedGoogle Scholar
  32. 32.
    LeRoith D, Clemmons D, Nissley P, Rechler MM (1992) NIH conference. Insulin-like growth factors in health and disease. Ann Intern Med 116: 854–862PubMedGoogle Scholar
  33. 33.
    LeRoith D, Adamo ML, Shemer J, Lanau F, Shen Orr Z, Yaron A, Roberts CT, Jr., Clemmons DR, Sheikh MS, Shao ZM, et al. (1993) Retinoic acid inhibits growth of breast cancer cell lines: the role of insulin-like growth factor binding proteins. Growth Regul 3: 78–80PubMedGoogle Scholar
  34. 34.
    Liu JP, Baker J, Perkins AS, Robertson FJ, Efstratiadis A (1993) Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75: 59–72PubMedGoogle Scholar
  35. 35.
    McGuire WLJ, Jackson JG, Figueroa JA, Shimasaki S, Powell DR, Yee D (1992) Regulation of insulin-like growth factor-binding protein (IGFBP) expression by breast cancer cells: use of IGFBP-1 as an inhibitor of insulin-like growth factor action. J Natl Cancer Inst 84: 1336–1341PubMedCrossRefGoogle Scholar
  36. 36.
    Minniti CP, Maggi M, Helman LJ (1992) Suramin inhibits the growth of human rhabdomyosarcoma by interrupting the insulin-like growth factor II autocrine growth loop. Cancer Res 52: 1830–1835PubMedGoogle Scholar
  37. 37.
    Mishra L, Voyles N, Bass B, et al (1993) Gene expression of IGFBP-2 is increased in human colorectal carcinoma. [Abstract] FASEB J 7: 2166Google Scholar
  38. 38.
    Moser DR, Lowe WL Jr, Dake BL, Booth BA, Boes M, Clemmons DR, Bar RS (1992) Endothelial cells express insulin-like growth factor-binding proteins 2 to 6. Mol Endocrinol 6: 1805–1814PubMedCrossRefGoogle Scholar
  39. 39.
    Muller HL, Oh Y, Gargosky SE, Wilson KF, Lehrnbecher T, Rosenfeld RG (1994) Insulin-like growth factor binding protein-3 concentrations and insulin-like growth factor binding protein-3 protease activity in sera of patients with malignant solid tumors or leukemia. Pediatr Res 35: 720–724PubMedGoogle Scholar
  40. 40.
    Nakatani A, Shimasaki S, Erickson GF, Ling N (1991) Tissue-specific expression of four insulin-like growth factor-binding proteins (1, 2, 3, and 4) in the rat ovary. Endocrinology 129: 1521–1529PubMedCrossRefGoogle Scholar
  41. 41.
    Nyman T, Pekonen F (1993) The expression of insulin-like growth factors and their binding proteins in normal human lymphocytes. Acta Endocrinol Copenh 128: 168–172PubMedGoogle Scholar
  42. 42.
    Ogawa O, Eccles MR, Szeto J, McNoe LA, Yun K, Maw MA, Smith PJ, Reeve AE (1993) Relaxation of insulin-like growth factor II gene imprinting implicated in Wilms' tumour. Nature 362: 749–751PubMedCrossRefGoogle Scholar
  43. 43.
    Orlowski CC, Brown AL, Ooi GT, Yang YW, Tseng LY, Rechler MM (1990) Tissue, developmental, and metabolic regulation of messenger ribonucleic acid encoding a rat insulin-like growth factor-binding protein. Endocrinology 126: 644–652PubMedGoogle Scholar
  44. 44.
    Rechler MM (1993) Insulin-like growth factor-binding proteins. Vitam Horm 47: 1–114PubMedCrossRefGoogle Scholar
  45. 45.
    Reiss K, Porcu P, Sell C, Pietrzkowski Z, Baserga R (1992) The insulin-like growth factor 1 receptor is required for the proliferation of hemopoietic cells. Oncogene 7: 2243–2248PubMedGoogle Scholar
  46. 46.
    Ren-Qiu Q, Ruelicke T, Hassam S, Haselbacher GK, Schoenle EJ (1993) Systemic effects of insulin-like growth factor-II produced and released from Wilms tumour tissue. Eur J Pediatr 152: 102–106PubMedCrossRefGoogle Scholar
  47. 47.
    Rutanen EM, Stenman S, Blum W, Karkkainen T, Lehtovirta P, Stenman UH (1993) Relationship between carbohydrate metabolism and serum insulin-like growth factor system in postmenopausal women: comparison of endometrial cancer patients with healthy controls. J Clin Endocrinol Metab 77: 199–204PubMedCrossRefGoogle Scholar
  48. 48.
    Sauerbrey A, Zintl F, Malke H, Reimann M, Maaser M, Domula M, Dorffel W, Eggers G, Exadaktylos P, Kotte W et al (1993) Results and experiences with a modified BFM protocol for treatment of recurrences in children with acute lymphoblastic leukemia in East German areas. Klin Padiatr 205: 281–287PubMedCrossRefGoogle Scholar
  49. 49.
    Smith SD, McFall P, Morgan R, Link M, Hecht F, Cleary M, Sklar J (1989) Long-term growth of malignant thymocytes in vitro. Blood 73: 2182–2187PubMedGoogle Scholar
  50. 50.
    Timme J, Mittler U, Mohnike K, Dörffel W. Einfluss verschiedener Therapieprotokolle auf das Wachstum und die Endgrösse von Kindern mit akuter lymphoblastischer Leukamie oder Non-Hodgkin-Lymphom. Klin Pad (in press)Google Scholar
  51. 51.
    Van der Does-van den Berg A, Bartram CR, Basso G, Benoit YC, Biondi A, Debatin KM, Haas OA, Harbott J, Kamps WA, Koller U, et al. (1992) Minimal requirements for the diagnosis, classification, and evaluation of the treatment of childhood acute lymphoblastic leukemia (ALL) in the “BFM Family” Cooperative Group. Med Pediatr Oncol 20: 497–505PubMedCrossRefGoogle Scholar
  52. 52.
    Wood TL, Streck RD, Pintar JE (1992) Expression of the IGFBP-2 gene in post-implantation rat embryos. Development 114: 59–66PubMedGoogle Scholar
  53. 53.
    Yateman ME, Claffey DC, Cwyfan Hughes SC, Frost VJ, Wass JA, Holly JM (1993) Cytokines modulate the sensitivity of human fibroblasts to stimulation with insulin-like growth factor-I (IGF-I) by altering endogenous IGF-binding protein production. J Endocrinol 137: 151–159PubMedCrossRefGoogle Scholar
  54. 54.
    Zhang LQ, Downie PA, Goodell WR, McCabe NR, LeBeau MM, Morgan R, Sklar J, Raimondi SC, Miley D, Goldberg A, et al (1993) Establishment of cell lines from B-cell precursor acute lymphoblastic leukemia. Leukemia 7: 1865–1874PubMedGoogle Scholar
  55. 55.
    Zumkeller W, Schwander J, Mitchell CD, Morrell DJ, Schofield PN, Preece MA (1993) Insulin-like growth factor (IGF)-I,-II and IGF binding protein-2 (IGFBP-2) in the plasma of children with Wilms' tumour. Eur J Cancer 29A: 1973–1977PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • Klaus L. Mohnike
    • 1
  • Ute Kluba
    • 1
  • Uwe Mittler
    • 1
  • Volker Aumann
    • 1
  • Peter Vorwerk
    • 1
  • Werner F. Blum
    • 2
  1. 1.Magdeburg, Zentrum für KinderheilkundeOtto-von-Guericke-UniversitätMagdeburgGermany
  2. 2.Abteilung Allgemeine Pädiatrie und OnkologieUniversitäts-Kinderklinik TübingenTübingenGermany

Personalised recommendations